Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-63274
Dees, Clara; Tomcik, Michal; Palumbo-Zerr, Katrin; Akhmetshina, Alfiya; Beyer, Christian; Lang, Veronika; Horn, Angelika; Zerr, Pawel; Zwerina, Jochen; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg H W (2012). JAK2 as a novel mediator of the pro-fibrotic effects of TGFβ in systemic sclerosis. Arthritis and Rheumatism, 64(9):3006-3015.
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OBJECTIVE.: Tissue fibrosis caused by a pathological activation of SSc fibroblasts is a major hallmark of systemic sclerosis (SSc). The aims of the present study were to investigate whether JAK2 contributes to the pathologic activation of fibroblasts in SSc and to evaluate the anti-fibrotic potential of JAK2 inhibition for the treatment of systemic sclerosis. METHODS.: Activation of JAK2 in human skin and in experimental fibrosis was determined by immunohistochemistry. JAK2 signaling was inhibited with the selective JAK2 inhibitor TG 101209 or by siRNA. Bleomycin-induced dermal fibrosis and tight-skin 1 (Tsk-1) mice were used to evaluate the anti-fibrotic potential of a specific JAK2 inhibition in vivo. RESULTS.: Increased activation of JAK2 was detected in the skin of SSc patients, particularly in fibroblasts. The activation of JAK2 was TGFβ dependent and persisted in cultured SSc fibroblasts. Inhibition of JAK2 reduced the basal collagen synthesis selectively in SSc fibroblasts but not in resting healthy dermal fibroblasts. Moreover, inhibition of JAK2 prevented the stimulatory effects of TGFβ on fibroblasts. Treatment with TG 101209 did not only prevent bleomycin-induced fibrosis, but also effectively reduced skin fibrosis in Tsk-1 mice. CONCLUSION.: We demonstrated that JAK2 is activated in a TGFβ dependent manner in SSc. Considering the potent anti-fibrotic effects of JAK2 inhibition, our study might have direct translational implications, because inhibitors of JAK2 are currently evaluated in clinical trials for myeloproliferative disorders and would be also available for evaluation in SSc patients.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
|DDC:||610 Medicine & health|
|Deposited On:||11 Jul 2012 09:38|
|Last Modified:||24 Dec 2012 05:53|
|Free access at:||Publisher DOI. An embargo period may apply.|
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